6-substituted estradiol derivatives and methods of use

Abstract

A compound having the structure: wherein R 1 , R 2 , R, R, X, Y and Z are as defined herein. The compounds are estrogen receptor modulators useful for the treatment of proliferative disorders.

1. A compound of the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , R 4  are independently selected from the group consisting of H, C 1 -C 6  alkyl, substituted alkyl, and halogen; 
 R 5  is selected from the group consisting of —NH 2 , —NH(CH 2 ) n OH, —NH(CH 2 ) n —COOsalt, —(NH)CH 2 OHCH 3 , —NHCOOH, and —CH 2 NHCOOH; 
 n is an integer from 1-7; 
 R 6  is selected from a group consisting of H, a C 1 -C 6  alkyl, a C 1 -C 6  substituted alkyl, a sulfate, a glucoronide, a phenyl or a substituted phenyl group, a cyclo- or heterocyclo group, and 
 R 7  is selected from the group consisting of H, a C 1 -C 6  alkyl, a C 1 -C 6  substituted alkyl, a halogen, a halogenated alkyl, a sulfate, a glucoronide, —SO 2 NH 2 , —COOH, —CN, —CHO, —COO salt and —NH 2 ; and 
 wherein the   symbol represents either a single or a double bond with the proviso that when the   symbol is a double bond and forms a keto group at position 17, then no R 6  is present. 
 
     
     
       2. The compound of  claim 1  of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       3. A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically-acceptable carrier, wherein said compound comprises at least one S enantiomer, R enantiomer, S diasteromer or R diasteromer.